A systematic review of procedural modalities in the treatment of notalgia paresthetica

Abstract Background Notalgia paresthetica (NP) is a rare condition characterized by localized pain and pruritus of the upper back, associated with a distinct area of hyperpigmentation. Given the lack of standardized treatment and the uncertain efficacy of available options, applying procedural methods is of growing interest in treating NP. Aims We sought to comprehensively evaluate the role of procedural treatments for NP. Methods We systematically searched PubMed/Medline, Ovid Embase, and Web of Science until November 14th, 2023. We also performed a citation search to detect all relevant studies. Original clinical studies published in the English language were included. Results Out of 243 articles, sixteen studies have reported various procedural modalities, with or without pharmacological components, in treating NP. Pharmacological procedures, including injections of botulinum toxin, lidocaine, and corticosteroids, led to a level of improvement in case reports and case series. However, botulinum toxin did not show acceptable results in a clinical trial. Moreover, non‐pharmacological procedures were as follows: physical therapy, exercise therapy, kinesiotherapy, acupuncture and dry needling, electrical muscle stimulation, surgical decompression, and phototherapy. These treatments result in significant symptom control in refractory cases. Physical therapy can be considered a first‐line choice or an alternative in refractory cases. Conclusion Procedural modalities are critical in the multidisciplinary approach to NP, especially for patients who are refractory to topical and oral treatments. Procedural modalities include a spectrum of options that can be applied based on the disease's symptoms and severity.


INTRODUCTION
Notalgia paresthetica (NP) is a type of neuropathy in the peripheral nervous system commonly observed in older females. 1 NP is identified by chronic pruritus of the medial scapular borders, often accompanied by pain and sensory abnormalities, such as stinging, numbness, or tingling. 2The affected region might be linked to a darkened patch, typically resulting from persistent scratching and rubbing to alleviate discomfort.Although the exact etiology of NP is still unknown, the condition may result from compression or damage to dorsal spinal nerves, particularly the upper segments spanning from T2 to T6. 3 In addition, various peripheral causes contribute to NP and can be categorized as physical, anatomical, genetic, metabolic, or infectious.Patients with NP do not develop primary lesions; however, secondary changes are seen as a result of continuous scratching.Moreover, the distinctive histopathological features of NP illustrated post-inflammatory melanosis, hyperkeratosis, and an inflammatory melanophage dermal infiltrate.
NP diagnosis is based on the patient's history and physical examination. 4Consequently, a misdiagnosis of NP adversely impacts the patient's quality of life, including their emotional well-being, sleep quality, and autonomy in managing their condition.Hence, having an accurate diagnosis and receiving effective treatment is imperative.The primary treatment for NP involves oral agents.Medications targeting gamma-amino-butyric acid (GABA), serotonin, histamine, and inflammation have been explored.Among these treatments, gabapentin is the most effective option in alleviating itching. 5Additionally, topical medications are utilized for NP treatment, such as capsaicin, steroids, anesthetics, amitriptyline/ketamine, and doxepin.Capsaicin stands out as the most frequent topical medication for NP with different administration routes, including cream, gel, lotion, solution, or patch with diverse concentrations.Topical capsaicin can provide immediate relief, but its effectiveness varies significantly over time. 6Topical steroids exhibit varying effectiveness and prove beneficial only when inflammation is present.Anesthetics, amitriptyline/ketamine, and doxepin are also not commonly employed in treating NP. 7 In addition to pharmacological medications, the utilization of procedural therapeutic options for NP treatment has increased in recent years.Initial reports indicated that botulinum toxin (BTX) could be a viable option, significantly improving itching. 8Moreover, local and intralesional injection of different substances, narrow-band ultraviolet B radiation (UVB), excimer lamp, and needling are recognized as alternative procedures that could be promising in treating NP. 2,7,[9][10][11] However, these approaches are currently unapproved for NP due to insufficient evidence regarding their effectiveness and safety.Consequently, assessing the effectiveness and safety profile of the available procedures can help clinicians find the best approach for treating NP patients.The current systematic review aims to evaluate the efficacy and safety of procedural treatment options for patients with NP.

MATERIAL AND METHODS
The current systematic review is based on the Preferred Reporting Item for Systematic Reviews and Meta-Analysis (PRISMA) 2020 statement. 12The checklists can be found in the Supplementary documents (Tables S1 and S2).

Search strategy
A comprehensive systematic search was conducted across three databases, PubMed/Medline, Ovid Embase, and Web of Science, from their inception until November 14th, 2023.A full list of keywords and MeSH terms is available in the Supplementary documents (Table S3).

Eligibility criteria and study selection
Clinical studies available in English full text were included in this systematic review.The source populations eligible for this study were individuals with NP of any age and gender who underwent any procedural treatment.Studies that used non-procedural treatments, review articles, guidelines, book chapters, in vitro/ex vivo studies, and animal studies were not eligible for inclusion.

Data extraction
Three investigators independently conducted the data extraction process for the selected articles (YG, HA, and FF).The process was as follows: (I) Extraction of study and patient characteristics, including author, year, design, sample size, gender, previous treatments, and type of procedural treatment.(II) Extraction of results, including outcome measurements, efficacy, safety, adverse events, and follow-ups.Moreover, any disagreements were resolved by the corresponding authors during the data extraction process.

Risk of bias assessment
Three reviewers (YG, NH, and AH) independently appraised the included studies' bias risk and methodological quality of included studies.For these evaluations, we used the National Institute of Health methodological quality assessment for the case series and case reports.
The risk of bias assessment results are illustrated in Tables S4-S7.

Search results
A total of 243 records were identified in a search conducted until November 14th, 2023.A number of 102 duplicates were found and removed subsequently.In the first and second steps of the screening process, the titles and abstracts of the remaining 141 records were reviewed.Disagreements that arose during the screening process were resolved through consensus with the third reviewer or the corresponding authors.The full texts of 14 articles were reviewed according to predefined eligibility criteria in the final phase of the screening.Moreover, two additional studies were included after the citation search.
Ultimately, 16 articles were included for data extraction in this system-atic review.The PRISMA flowchart of the inclusion process is depicted in Figure 1.

Pharmacological procedures
A total of eight articles have investigated the efficacy and safety of pharmacological procedures, including four articles on BTX-A injection, one study on Rbtx-B injection, two articles on lidocaine injection, and one study on intralesional triamcinolone acetonide injection.
In a study conducted by Pérez-Péreze et al. 2 on five patients with NP, none of the patients experienced a decrease in pruritus; the disease relapsed in three patients after one month, and pruritus was exacerbated in two patients.According to a randomized controlled trial carried out by Maari et al. 17  Intralesional triamcinolone acetonide was found to be effective in a case series reported by Özcan et al., 11 with respect to 100% improvement in itch scores in 33% of patients.Also, numbness and tingling in two patients after the first injection were reduced.Regarding safety, self-limited skin atrophy occurs in all patients as an adverse event.

Non-pharmacological procedures
A total of eight studies have evaluated non-pharmacological procedures' efficacy and safety in the management of NP.In a study conducted by Karasel et al., 21 11 patients underwent different types of physical therapy, including hot pack, transcutaneous electrical nerve stimulation (TENS), and ultrasound therapy; seven of the subjects received dry needle therapy; four patients undertook a home exercise program (stretching and resistance exercises); and three of the patients underwent kinesiotherapy.The results demonstrated a significant decrease in VAS and douleur neuropathique 4 (DN4) scores from the baseline and a reduction in pain levels in TENS therapy cases.Conventional TENS therapy in another study recruiting 15 patients was correlated with a significant decline in the mean pruritus score after the treatment. 22Additionally, Ba gcıer et al. 10 noted a significant drop in the DN4 and the 5-D itch scale scores in an NP patient after three sessions of dry needling therapy.
In another investigation by Fonda-Pascual et al., 9 utilizing a 308 nmexcimer lamp in 11 patients with NP resulted in a significant global reduction in VAS and pruritus with no relapse after six months of follow-up.Moreover, the procedure was safe except for inducing variable hyperpigmentation.Likewise, UVB narrow-band application in five peers with NP was associated with substantial improvement in pruritus in all cases. 23Acupuncture application in 16 patients led to complete amelioration of itching in 12 and partial relief in four patients. 24However, six subjects experienced exacerbation after seven months and needed additional acupuncture therapy.EMS implementation in a group of four cases was associated with rapid alleviation of pain, as reported by Wang et al. 25 However, the pain relapsed after EMS cessation for an extended period.Based on a case report by Williams et al., 26 surgical decompression resulted in a 50% reduction in original pain in the 1st week.The patient was also free of symptoms four months after surgical treatment.

DISCUSSION
NP is a sensory neuropathy characterized by localized pain, pruritus, paresthesia, and numbness in the back. 21The chronic nature of NP, consisting of remissions and flare-ups, can negatively influence the patient's quality of life.Hence, it is imperative to correctly recognize and treat NP, particularly as it is reported to be underdiagnosed in several cases. 27The exact etiology of NP is still uncertain; however, it is suggested that a multifactorial process involving muscle impingement, increase in dermal innervation, and any spinal pathology may contribute to the progression of this condition by affecting the posterior cutaneous branches of T2-T6 spinal nerves. 28Following chronic rubbing and scratching to relieve the discomfort, hyperpigmented patches and lichenification appear on the affected part of the back.Considering dermatological or neuromuscular aspects of NP, clinicians consider various therapeutic strategies to alleviate clinical signs and symptoms with different levels of success. 27Therapeutic strategies for NP have been widely adapted from options utilized for other neuropathic pain conditions. 20Treatment options range from topical agents and systemic medications to several procedural modalities with or without pharmacological components.Nevertheless, no treatment guidelines exist for NP, and the efficacy of these options remains unclear.
Current evidence shows topical medications and physical therapy are used as first-line treatments, followed by systemic agents in unresponsive or intolerant patients, and procedural modalities and surgical management for refractory cases of NP. 27 Topical agents, including capsaicin, tacrolimus, and local anesthetic creams, are considered firstline treatments to decrease pruritus.Nonetheless, topical medications are limited due to their partial effectiveness, failure of long-term response, and adverse events that influence patient capacitance. 29In these cases, oral treatment options, such as gabapentin, oxcarbazepine, and amitriptyline, are prescribed.Unlike topical agents, the tolerability of oral medications was found to be acceptable.Although treatment with gabapentin successfully resulted in symptom relief, 5 the effectiveness of drugs targeting serotonin, histamine, and inflammation was limited. 30Besides, maintenance dosing for long-term use, systemic adverse reactions, possible drug interactions, and relapse after treatment cessation are among the limitations of oral pharmacological choices. 5,27,31 recalcitrant cases of NP, the application of procedural treatments led to diverse levels of response.Procedural modalities are divided into pharmacological and non-pharmacological procedures.Pharmacoprocedural treatments for NP include injections of lidocaine, BTX, and corticosteroid injections.On the other hand, procedural modalities without a pharmacological component were as follows: physical therapy, exercise therapy, kinesiotherapy, acupuncture and dry needling, EMS, surgical decompression, and phototherapy.
BTX-A is a type of purified protein that cleaves synaptosomalassociated proteins of 25 kDa (SNAP-25) and inhibits the release of acetylcholine at the neuromuscular junction.Studies yielded different levels of efficacy regarding the results of BTX-A injections.In detail, long-lasting, complete resolution of symptoms was detected in several cases, 8,18 while clinical trials demonstrated no difference between BTX-A and saline placebo. 17In addition to BTX-A, intradermal injections of Rbtx-B substantially reduced pain and paresthesia in patients with NP and other types of focal painful neuropathies. 19The efficacy of BTX is due to its impact on suppressing the release of glutamate, noradrenaline, and a mediator of pain and itch called substance P from afferent C fibers of dorsal root ganglion neurons. 18It is imperative to note that the dose of BTX shall be adjusted for each patient based on the size of the hyperpigmentation and symptomatic region. 27reover, multiple treatment sessions might be mandatory to achieve optimum relief of symptoms. 32rthermore, lidocaine has been utilized for NP not only as a topical cream but also as IV infusions, local intradermal injections, and deeper injections resulting in dorsal spinal nerve block. 7,20,33Lidocaine has been largely applied in the management of both acute and chronic pain as it blocks voltage-sensitive sodium channels, leading to suppression of peripheral and central pain transmission.Recent investigations have also shown the involvement of the immune system, calcium and potassium channels, and N-methyl-D-aspartate receptors.
Some studies found that the effect of lidocaine on itching was more noticeable than its pain management properties. 20However, further investigations are warranted to confirm these findings.
Similar to lidocaine, corticosteroids in different forms and routes of administration have been widely used for several conditions with neuropathic itch, including NP. 11 In addition to suppressing spontaneous and ectopic discharges from injured nerves, corticosteroids exert short-lasting inhibitory properties on transmission in normal C fibers. 34Previous studies reported that topical corticosteroids did not significantly affect NP, and their efficacy was limited to NP cases associated with secondary inflammation. 31However, procedural treatment with corticosteroids (paravertebral block with methylprednisolone acetate and bupivacaine as well as intralesional triamcinolone acetonide injections) successfully controlled NP-associated pruritus. 6,11veral non-invasive procedures, such as physiotherapy, manipulative therapy, acupuncture and dry needling, analgesic electric currents, and traction, were successful in alleviating NP symptoms, including pain and itch. 10,21,24Physical therapy acts through musculoskeletal factors, leading to long-lasting symptomatic improvement. 27In detail, these approaches mainly aim to reduce the compression of the dorsal branch of spinal nerves by decreasing the edema around the nerves, relaxing the muscles, and inducing the release of opioid peptides in the dorsal horn, which prohibits nociceptive information release. 24ysical treatments can be applied as a first-line choice in some patients or can be combined with other options to enhance the treatment response.In cases who were unresponsive to the treatments mentioned above, surgical management can effectively resolve pain. 26reover, phototherapy and light-based modalities led to a level of pruritus improvement.NB-UVB is able to diminish the count of epidermal nerve fibers, which may be elevated locally in patients with NP. 23 However, in patients with severe and chronic NP, innervation is decreased in the affected skin parts.Furthermore, the wavelength of the 308-nm excimer lamp is similar to NB-UVB. 9Another advantage of a 308-nm excimer lamp is that it acts locally on a specific area, unlike NB-UVB, which needs dose adjustment and imposes unnecessary irradiation on the patient.
It is important to note that NP is a rare condition; therefore, the studies assessing the treatment options have a small sample size and limited evidence.Besides, NP patients are diagnosed with diverse clinical symptoms and treated by a wide range of subspecialists.Procedural modalities have a significant role in the management of NP symptoms and can be used as first-line, second-line, and last-line options.
However, the effectiveness is still doubtful and needs to be studied in large-scale clinical trials with the control group.

CONCLUSION
NP is a chronic condition with sensory abnormalities presenting with pruritus of the medial scapular borders, often accompanied by pain and post-inflammatory hyperpigmentation.
Considering the multifactorial etiology of NP, its diagnosis and management necessitate a multidisciplinary approach.The importance of procedural modalities in NP is due to their ability to provide targeted relief, especially when topical and oral medications fail to offer adequate symptom control.Aside from topical and oral treatments, physical therapy can be considered as a first-line option in some cases.
Furthermore, pharmacological procedures and phototherapy are useful in reducing itching.It is imperative to consider that investigations on NP treatment are mostly small-sized due to its rarity.Hence, larger-scale clinical trials with long-term follow-up are required.

F I G U R E 1
PRISMA 2020 flow diagram for new systematic reviews, which included searches of databases, registers, and other sources.(NIH) Quality Assessment Tool for Clinical Trials, 13 NIH for Before-After (Pre-Post) Studies with No Control Group, 14 NIH for Observational Cohort and Cross-Sectional Studies, 15 and Murad et al. 16 on 20 subjects suffering from NP, there was no statistically significant difference in pruritus Visual analog scale (VAS) between patients treated with BTX-A and those given a placebo after eight weeks of treatment.In another study performed by Wallengren et al.,8 four patients underwent various units of BTX-A.The findings revealed a mean improvement of 28% in the VAS score.Of two patients who reported improvement after six weeks, one reported a VAS of 45%, while the other was still free from itch after 18 months of follow-up.Weinfeld et al.18 investigate two patients receiving different BTX-A units.One of them remains completely symptom-free after more than 18 months following treatment, and the hyperpigmentation on her back was barely perceptible.Moreover, the other case showed significant improvement in the clinical manifestations after the first injection.Further, an investigation by Grogan et al.19 on three cases with NP who were taking intradermal Rbtx-B depicted a substantial reduction in pain and paresthesia in most patients as well as a reduction in VAS scores by an average of 4.3 points before and after injections.In terms of safety, all types of BTX demonstrated a favorable safety profile without causing adverse events.Additionally, two studies evaluated the lidocaine efficacy and safety in NP cases.Regarding the study by Mülko glu et al.,7 the VAS-pruritus score decreases in the 2nd and 4th weeks following lidocaine injection.Moreover, Chtompel et al.20 reported a case with NP who demonstrated a 90% improvement in itch, lasting seven days after the first infusion and ten days after the second infusion, following lidocaine IV injection.The patient also experienced a 20% reduction in itch severity after recurrence compared to the baseline.

ID Design of study Sample size Gender Previous treatment (s) Treatment Outcome measurement Efficacy Safety and adverse events Follow-up Karasel, 2022
Characteristics of eligible studies utilized procedural modalities in the treatment of notalgia paresthetica.